重组热点悖论:PRDM9及其靶位点的协同进化

IF 1.2 4区 生物学 Q4 ECOLOGY
Francisco Úbeda , Frédéric Fyon , Reinhard Bürger
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引用次数: 0

摘要

重组通常集中在被称为重组热点的小区域,那里的重组远高于基因组的平均水平。在包括人类在内的许多脊椎动物中,基因PRDM9指定哪些DNA基序将成为启动重组的断裂的目标,最终决定重组热点的位置。因为断裂(允许重组)的序列被转换为不断裂(阻止重组)的顺序,后一个序列被过度传递给后代,重组热点是自我破坏的。鉴于其自毁性质,重组热点最终应该在发现它们的基因组中灭绝。虽然经验证据表明,随着时间的推移,单个热点确实会变得不活跃(死亡),但热点在许多脊椎动物中都很丰富:这一矛盾被称为重组热点悖论。是什么使重组热点免于其预言的灭绝?在这里,我们建立了一个序列特异性基因转换、生育能力选择和复发突变之间相互作用的共同进化模型。我们发现等位基因频率振荡导致稳定的极限环。从生物学的角度来看,这意味着当生育能力选择弱于基因转换时,它不能阻止单个热点的死亡,但可以通过驱动它们的重新激活(复苏)来拯救它们免于灭绝。在我们的模型中,突变平衡了热点的死亡和复苏,从而在进化过程中保持了它们的数量。有趣的是,我们发现多个等位基因导致混沌振荡,而多个靶点导致靶点之间异步振荡,从而有助于保持平均基因组重组概率不变。此外,我们发现PRDM9的表达水平应该控制作为热点的靶标的比例和基因组的整体温度。因此,我们的共同进化模型提高了我们对热点如何被替换的理解,从而有助于解决重组热点悖论。从更实用的角度来看,我们的工作提供了关于突变概率和生育选择与热点预期寿命之间关系的可测试预测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Recombination Hotspot Paradox: Co-evolution between PRDM9 and its target sites

Recombination often concentrates in small regions called recombination hotspots where recombination is much higher than the genome’s average. In many vertebrates, including humans, gene PRDM9 specifies which DNA motifs will be the target for breaks that initiate recombination, ultimately determining the location of recombination hotspots. Because the sequence that breaks (allowing recombination) is converted into the sequence that does not break (preventing recombination), the latter sequence is over-transmitted to future generations and recombination hotspots are self-destructive. Given their self-destructive nature, recombination hotspots should eventually become extinct in genomes where they are found. While empirical evidence shows that individual hotspots do become inactive over time (die), hotspots are abundant in many vertebrates: a contradiction called the Recombination Hotspot Paradox. What saves recombination hotspots from their foretold extinction? Here we formulate a co-evolutionary model of the interaction among sequence-specific gene conversion, fertility selection, and recurrent mutation. We find that allelic frequencies oscillate leading to stable limit cycles. From a biological perspective this means that when fertility selection is weaker than gene conversion, it cannot stop individual hotspots from dying but can save them from extinction by driving their re-activation (resuscitation). In our model, mutation balances death and resuscitation of hotspots, thus maintaining their number over evolutionary time. Interestingly, we find that multiple alleles result in oscillations that are chaotic and multiple targets in oscillations that are asynchronous between targets thus helping to maintain the average genomic recombination probability constant. Furthermore, we find that the level of expression of PRDM9 should control for the fraction of targets that are hotspots and the overall temperature of the genome. Therefore, our co-evolutionary model improves our understanding of how hotspots may be replaced, thus contributing to solve the Recombination Hotspot Paradox. From a more applied perspective our work provides testable predictions regarding the relation between mutation probability and fertility selection with life expectancy of hotspots.

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来源期刊
Theoretical Population Biology
Theoretical Population Biology 生物-进化生物学
CiteScore
2.50
自引率
14.30%
发文量
43
审稿时长
6-12 weeks
期刊介绍: An interdisciplinary journal, Theoretical Population Biology presents articles on theoretical aspects of the biology of populations, particularly in the areas of demography, ecology, epidemiology, evolution, and genetics. Emphasis is on the development of mathematical theory and models that enhance the understanding of biological phenomena. Articles highlight the motivation and significance of the work for advancing progress in biology, relying on a substantial mathematical effort to obtain biological insight. The journal also presents empirical results and computational and statistical methods directly impinging on theoretical problems in population biology.
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